Cardiac rhythm disturbances are a major cause of morbidity and even mortality in our ageing population. Most of these rhythms are based on reentry, i.e. the continuous circulation of a wavefront of excitation around a functional or anatomical circuit such atrial fibrillation and flutter. Atrial fibrillation could exist as a stable state, self-sustained and independent of its initiating trigger in the presence of non-uniform distribution (i.e. dispersion) of atrial refractory periods. In addition, maintenance of atrial fibrillation may require a critically short wavelength in order to sustain reentry. However, the cellular and pathophysiological mechanisms in the initiation and maintenance of atrial fibrillation remain poorly understood. It has been reported that inducibility and maintenance of this atrial arrhythmia are associated with an increased dispersion in atrial refractoriness. In addition, alterations in the electrophysiologic properties of the atria affecting wavelength may led to persistence of atrial fibrillation and to the occurrence of reentrant atrial arrhythmias in both in vitro and in vivo models. Furthermore, electrical remodeling of the atria may also increase the likelihood to the maintenance of this atrial arrhythmia.
Electrophysiological studies suggest that the mechanism of type I atrial flutter in humans and in canine models involves a macroreentrant circuit around an anatomically or anisotropically defined obstacle with either a partially or fully excitable gap. The excitable gap is one of the determinant of the continued circulation of the abnormal atrial impulse and in its presence an extrastimulus may excite the circuit and reset the tachycardia. Furthermore, the persistent circulation of this wavefront is determined by the effective refractory period, the conduction velocity, the wavefront and the nature and duration of the excitable gap, i.e. that portion of the circuit which has partially or fully recovered its excitability. This excitable gap, in part, determined by the size of the reentry circuit and the electrophysiological properties of its tissue components.
However, external influences may also significantly modify the susceptibility for the occurrence of atrial arrhythmias via different electrophysiological mechanisms such as the excitable gap characteristics, the effective refractory period duration and dispersion, the conduction velocity, the wavefront duration and propagation forms and the number of the wavelets. Autonomic nervous system tone may implicitly have a role in the pathogenesis of initiation and persistence of supraventricular arrhythmias. In experimental models, both vagal stimulation and acetylcholine application to the heart can nonhomogeneously shorten atrial refractory period and produce either paroxysmal atrial arrhythmia, flutter or fibrillation. In man, the onset of atrial fibrillation has a diurnal distribution with a statistically significant peak occurring at night which correlates with an immediately preceding increase in vagal drive. Catecholamine administration (Isoproterenol) also shortens the atrial action potential and stimulation of sympathetic nerves shortens atrial refractoriness and increases its dispersion facilitating the induction of atrial fibrillation. In man, attacks of atrial fibrillation have also been reported to be associated with adrenergic activation. Little is known, however, on the possible influence of autonomic nervous system tone on an established stable reentry circuit such as is seen in atrial flutter, an arrhythmia which is frequently difficult to interrupt by pharmacological means, and also on the occurrence of the leading circle phenomena during atrial fibrillation episodes. In a human study of parasympathetic and sympathetic blockade, observations limited to effects on atrial flutter cycle length did not detect any change either in the supine or upright position. No study has yet addressed the effects of autonomic neurotransmitters on the refractory period, duration and composition of the excitable gap and thus, on the viability of an atrial reentry circuit.
Despite considerable advances in our understanding on the mechanism of this atrial arrhythmia, antiarrhythmic drug therapy to produce and maintain sinus rhythm is fraught with a variety of problems. These drugs are either incompletely effective, may have proarrhythmic properties, and also may increase mortality. Since some of the more dangerous proarrhythmic potential of antiarrhythmic drugs appears to be related to sodium channel blocking properties, there has been increased interest in class III drugs, which act by increasing action potential duration and refractoriness without blocking sodium channels. The pharmacological control of cardiac arrhythmias using class III antiarrhythmic drugs which prolong the cardiac action potential has gained interest recently, particularly in view of reports of proarrhythmic and increased mortality associated with the use of class I antiarrhythmic drugs in the treatment of both ventricular and atrial arrhythmias. In addition, there is evidence that drugs with class III antiarrhythmic action may be more effective than the class I antiarrhythmic drugs for conversion and suppression of some cardiac arrhythmias, particularly those due to reentry. This greater efficacy of the class III antiarrhythmic drugs may be due in part to their ability to selectively prolong refractoriness and wavelength and reduce dispersion of refractoriness. Despite extensive investigation in the past, the critical electrophysiologic determinants of antiarrhythmic drug efficacy in specific reentrant tachycardias are not fully delineated. Sotalol is one such class III antiarrhythmic drugs which can exist in either the d- or l-isomer forms. Both isomers have equal class III activity but only the l-isomer possesses significant xcex2-adrenoceptor blocking activity. d,l-Sotalol, the racemic, therefore has both class II and class III properties. It has been used both to terminate atrial arrhythmias and to prevent their recurrence following cardioversion. It blocks both the slow and rapid component of the delayed rectifier potassium current (Iks and Ikr) and thus increases the atrial action potential duration and the atrial effective refractory period. At high concentrations, Sotalol can also inhibit the background or inward rectifying K+ (Ikl) and decreases the transient outward K+ current (Ito). Administration of class III antiarrhythmic drugs has been reported to prevent and/or terminate atrial flutter and fibrillation, an effect correlated with a shortening of the excitable gap and with prolongation of both the atrial arrhythmias cycle length and the refractory period.
The purpose of this invention is to determine the effects of norepinephrine and acetylcholine on the excitable gap composition during a sustained stable atrial flutter, and on the atrial effective refractory period duration and dispersion, atrial conduction velocity and atrial wavelength. Furthermore, this invention illustrates also the influence of autonomic nervous system activation and neurotransmitters infusion on the occurrence of these atrial arrhythmias, and whether these significant effects could alter those of sotalol on the same electrophysiological parameters. This invention also project the possibility for new atrial targets for the use of catheter ablation during the treatment of atrial arrhythmias. These new targets for catheter ablation during an atrial arrhythmia may be the fully excitable tissue, and/or the areas with the greatest density of parasympathetic innervation such as the tissues near the sinoatrial nodal fat pad and septal.
Atrial arrhythmias, a major contributor to cardiovascular morbidity, are believed to be influenced, activated and aggravated by autonomic nervous system tone. Furthermore, the treatment of this atrial arrhythmias are influenced, threaded and degenerated to a proarrhythmic events under the dominant effects of the autonomic nervous system activation. This invention evaluated the significance of sympathetic and parasympathetic activation by determining the effects of norepinephrine and acetylcholine on the composition of the excitable gap during a stable sustained atrial flutter, on the effective refractory period, on the conduction velocity, and on the wavelength in a canine model of stable atrial flutter. We also evaluated whether norepinephrine and acetylcholine administration can alter class III antiarrhythmic drug effects in the occurrence of atrial arrhythmias. This invention also evaluated the significance of sympathetic and parasympathetic denervation and activation by determining the direct effects of right and left stellar ganglions (10 Hz, 2 ms) and right vagal (1 Hz, 0.1 ms) stimulation on the atrial effective refractory period duration and dispersion, on the atrial conduction velocity, on the atrial wavelength and on the viability of the occurrence of atrial fibrillation. This invention also evaluated whether the autonomic nervous stimulation can alter class III antiarrhythmic drug (sotalol) effects in the same electrophysiological parameters described above and on the occurrence of these atrial arrhythmias.
In a group of 13 open chest anaesthetised dogs, atrial flutter model was produced during baseline conditions around the tricuspid valve using a Y-shaped lesion in the intercaval area extending to the right atrial appendage. Atrial flutter was induced at the shortest effective refractory period site using fast pacing stimulation (S1S1) of 100-150 ms. This manoeuvre was repeated as much as necessary with more damage in the Y-shaped lesion model to achieve a sustained stable atrial flutter ( greater than 10 min) during the baseline conditions. In order to determine the excitable gap duration and composition during this sustained and stable atrial flutter, a diastole was scanned with a single premature extrastimulus, S1S2 (S1S2=]refractory period, flutter cycle length[) to define the atrial flutter circuit composition and duration (flutter cycle length=refractory period+excitable gap). Atrial flutter cycle length, atrial effective refractory period and duration of the excitable gap were then determined. Measures were repeated during a constant infusion into the right coronary artery of norepinephrine (15 xcexcg/min) and acetylcholine (2 xcexcg/min) allowing 15 min for recovery from norepinephrine effects. The effects of norepinephrine and acetylcholine at a constant plasma level of d-sotalol or d,l-sotalol (0.8 mg/kg+0.4 mg/kg/hr) were also studied in 2 different groups of chloralose anaesthetised dogs on the same electrophysiological parameters described above.
In a group of 14 anaesthetised open chest dogs, atrial fibrillation was induced by fast pacing and up to 10 attempts of arrhythmia initiations during baseline condition, vagal denervation, right and left vagal stimulation #1 (1 Hz, 0.1 ms), right and left stellar ganglions denervation, right and left vagal stimulation #2 (1 Hz, 0.1 ms), right and left stellar ganglions stimulation (10 Hz, 2 ms), and right and left vagal stimulation (1 Hz, 0.1 ms) associated with right and left stellar ganglions stimulation (10 Hz, 2 ms). Under the same conditions described above, the effective refractory period duration and dispersion (at S1S1=200 ms), the conduction velocity and the wavelength are determined. Atrial fibrillation occurrence was evaluated by the mean duration of 10 atrial fibrillation episodes at baseline (for a group of animals when none of the 10 atrial fibrillation episodes at baseline were lasting more than 3 minutes) and following each of the conditions described above.
In summary, both neurotransmitters infusions (acetylcholine greater than  greater than norepinephrine) significantly increased the occurrence of the initiation of atrial flutter and decreased the duration of its maintenance by rapid (less than 2 minutes) conversion to a non sustained atrial fibrillation and then to a sinus rhythm state. Both neurotransmitters significantly increased the safety margin of excitability ahead of the wavefront and decreased the effective refractory. Autonomic and, in particular, vagal effects significantly diminish the action of pure class III antiarrhythmic drug, d-sotalol. However, in the presence of d,l-sotalol, a class III combined with anti-adrenergic effects, only acetylcholine still completely reversed its electrophysiological effects. This suggests that class III antiarrhythmic drugs with class II properties could resist the effects of sympathetic but not that of vagal activation. The effects of autonomic nervous system stimulation also significantly increased the occurrence of atrial fibrillation initiation and persistence. The effects of vagus activation significantly exceed those of sympathetic on the occurrence of atrial fibrillation, on the atrial effective refractory period duration and dispersion, on the conduction velocity and on the wavelength. In a particular interest, when the stellar ganglions denervation facilitates the occurrence of the initiation of a non sustained atrial fibrillation following the premature stimulation (S1S2) (data described the relation between initiation vs. duration of atrial fibrillation are not presented in this invention), the vagal denervation significantly reduced its initiation and maintenance. Furthermore, in the presence of class III drug therapy, the vagal stimulation significantly and markedly reversed the antiarrhythmic therapeutic effects of d,l-sotalol. These results demonstrate an absolute and emergent need to consider the effects of the presence and of the activation of parasympathetic nervous system tone during the pharmacological treatment of atrial arrhythmias. In addition, this invention targets the areas with the greatest density of parasympathetic innervation for ablation, such as the areas located near the sinoatrial nodal fat pad and septal, for the treatment of atrial arrhythmias during a catheter ablation manner.